RU2333014C2 - Dry powder inhaler - Google Patents

Abstract

FIELD: medical equipment.

SUBSTANCE: dry powder inhaler contains a nozzle, a substrate, a dose of the medicinal powder providing for disaggregating and dispersion of units of particles of a dose of a medicinal powder in air. Under the influence of air absorption force through a nozzle, particles of therapeutic powder dose, accessible to a nozzle, are gradually disaggregated and also dissipated in a stream of air coming in to a nozzle. Gradual disaggregation and dispersion is produced by effect of cutting a powder by air stream due to the relative movement induced between a nozzle and a powder dose. The nozzle is usually settled down outside a space filled with powder, without access to powder until the air stream in the nozzle framed by means of absorption passes threshold rate of a current. Simultaneously with absorption, relative movement begins so that the nozzle gradually crosses a powder dose. The cutting off effort and inertia of an air stream are so powerful that units of particles of a powder dose, which are close to an inlet opening of a moving nozzle, are liberated, disaggregated to a very high degree and dissipated, being carried away by the air stream created passing, through the nozzle, to a user.

EFFECT: invention does not require energy sources other than energy of effort of inspiration to realise a very high degree of disaggregation and effective dispersion in air of a therapeutic dose of a dry powder.

7 cl, 3 tbl, 18 dwg

Description

FIELD OF TECHNOLOGY

The present invention relates to a dry powder inhaler containing a nozzle, a substrate, a dose of a medicinal powder, which provides for the disaggregation and dispersion of airborne particle dose particle aggregates into the air.

BACKGROUND OF THE INVENTION

Currently, in medical services, the administration of drugs is carried out in a number of different ways. For a number of reasons, such as the need for topical treatment of pulmonary diseases in return for injection therapy and the need for a quick onset of action, there is great interest in administering drugs to the patient's lungs. Many different devices for delivering drugs to the lung have been developed, such as pressurized aerosols (pMDI (metered dose aerosol inhalers)), nebulizers and dry powder inhalers (DPI).

Despite the fact that inhalation of drugs is well established for the local treatment of pulmonary diseases, such as asthma, studies on the use of the lung as a possible injection site for systemically acting drugs are ongoing. For topically acting drugs, the preferred deposition of the drug in the lung depends on the location of the particular disease, therefore, deposition in the upper as well as in the lower respiratory tract is of interest. For systemic drug delivery, drug deposition deep in the lung is preferred and is usually necessary for maximum effectiveness. “Deep in the lung” should be understood as the peripheral regions of the lung and alveoli, where direct transport of the active substance into the blood can take place.

The lung is an attractive place for systemic drug delivery, as it provides a large surface area (approximately 100 m ² ) for absorption of molecules through the thin epithelium, which makes it possible to quickly absorb the drug. Therefore, pulmonary delivery has an advantage over nasal delivery, namely the possibility of achieving a sufficiently high degree of absorption without the need to use suction amplifiers. The suitability of this route of administration for a particular drug depends, for example, on the size of the dose and the degree of absorption of the particular substance.

Critical factors for the deposition of respirable particles in the lung are the nature of the inspiration / expiration and the distribution of particles according to their aerodynamic size. For maximum deposition in the lung, inhalation should be carried out calmly to reduce air velocity and, accordingly, reduce deposition in the upper respiratory tract under the influence of shock force.

For dry powder inhalers, there are restrictions on the aerodynamic particle size of the drug to achieve acceptable deposition of the drug inside the lung. If the particle is supposed to fall deep into the lung, then the aerodynamic size of the particles should usually be less than 3 microns, and for local deposition in the lung, usually about 5 microns. Larger particles settle in the mouth and throat. Thus, regardless of whether the goal is local or systemic drug delivery, it is important to keep the distribution of dose particles over their aerodynamic sizes within narrow limits to ensure a high percentage of the actually deposited dose where it will be most effective.

Disaggregation

Powders with a particle size suitable for inhalation therapy tend to aggregate, that is, to form small or large aggregates that must first be disaggregated and then introduced into the airways of the user. Disaggregation is defined as the destruction of aggregated powder through the use of energy, such as electrical, mechanical, pneumatic or aerodynamic energy. Some dry powder inhalers are designed for external sources of disaggregating energy, such as mechanical, electrical or pneumatic, and some are designed only for the strength of the inspiration of the user.

The aerodynamic diameter of a particle is the diameter of a spherical particle having a density of 1 g / cm ³ , which has the same inertial properties in air as the particle of interest. This means that the aerodynamic diameter of a particle is determined by the size of the original particle, the shape of the particle, and the density of the particle. If the initial particles are not completely disaggregated in the air, the unit will aerodynamically behave like one large particle. Therefore, for a particular drug substance, there are three main, fundamentally different ways to control the distribution of particles according to their aerodynamic size from a dry powder inhaler (DPI): a) by varying the distribution of the initial particles in size or b) by varying the degree of disaggregation, or c) by varying the particle density (making particles similar to tumbleweed).

Current inhalation devices for treating asthma and other pulmonary diseases typically deliver dispersed drug in a range of aerodynamic sizes suitable for local deposition in the lungs. Such a distribution of particles according to their aerodynamic sizes is often caused by ineffective disaggregation of the powder with the size of the initial particles within 2-3 microns. Thus, the inhaled dose consists mainly of aggregates of particles. This causes a number of disadvantages, the most important of which are:

- the uniformity of the distribution of particles by their aerodynamic dimensions can vary significantly from dose to dose, since disaggregation is sensitive to the most insignificant differences in inspiration from one inhalation to another;

- the distribution of particles of the delivered dose by their size may have a “tail” of large aggregates that will settle in the oral cavity and in the upper respiratory tract.

A better, more stable situation is obtained with a high degree of disaggregation of the drug powder in the inhaled air, since good disaggregation gives better reproducibility and efficiency of drug deposition in the lung. Preferably, the disaggregation system should be as less sensitive as possible to the inspiratory force produced by the user so that the distribution of the delivered particles by their aerodynamic dimensions in the inhaled air does not depend on the inspiratory force.

Therefore, for the effective delivery of drugs to the lung, there is a need for a system that stably generates a very high degree of disaggregation of drug powder in cases where the patient's inspiratory force varies within reasonable limits. Obviously, for systemically active drugs, when deep deposition in the lungs is required, as well as for locally acting drugs, when local deposition in the lungs is preferable to a greater degree, a stable high degree of disaggregation of the drug powder is an advantage. In this way, the distribution of particles by their aerodynamic size will be less dependent on the inspiratory strength of the user. The average particle size, which affects the deposition pattern in the lung, can be controlled by the size distribution of the initial particles in the powder. The larger initial particle size and perfect disaggregation provide a sustainable system for local delivery to the lung.

A very high degree of disaggregation requires the following:

- an appropriate powder preparation (particle size distribution, particle shape, adhesive forces, density, etc.);

- accordingly formed dose of the powder, adapted to the capabilities of the selected inhalation device;

- an inhalation device that provides a dose-cutting force of sufficient force to disaggregate the powder (for example, turbulence, collision).

As for the drug, there are a number of well-known methods for achieving a suitable distribution of the initial particle size, providing the possibility of proper deposition in the lungs of a high percentage of the dose. Such methods include jet grinding, spray drying and supercritical crystallization.

There are also a number of well-known methods for modifying the forces between particles and in this way to obtain a powder with suitable adhesive forces. Such methods include modifying the shape of the particles and the surface properties of the particles, for example, porous particles and controlled formation of powder granules, as well as adding an inert carrier with a large average particle size (the so-called ordered mixture).

Most locally available medications for inhalation currently available are fairly small organic molecules. Examples of medications used are steroids such as budesonide, bronchodilators such as salbutamol, and the like.

For many of these drugs, the development of pharmaceuticals is quite simple. On the other hand, new drugs for both local and systemic delivery often contain biological macromolecules with completely new requirements for the preparation of the drug.

Many proteins and peptides are potentially suitable for inhalation therapy and some of them are at different stages of development. Some examples are insulin, an alpha-1 proteinase inhibitor, interleukin-1, parathyroid hormone, genotropin, colony-stimulating factors, erythropoietin, interferons, calcitonin, factor VIII, alpha-1-antitrypsin, follicle-stimulating hormones, LHRH agonist ) and IGF-I (insulin-like growth factor I).

Protein and peptide drugs (PPDs) have properties that create significant problems in the preparation of the drug. In particular, their chemical and enzymatic lability practically does not allow the possibility of obtaining traditional dosage forms, such as oral tablets. Therefore, PPDs are currently administered predominantly parenterally by intravenous, intramuscular or subcutaneous injection. Although these routes are usually satisfactory for a limited number of administrations, problems with long-term therapy exist. Frequent injections needed to treat the disease, of course, are not an ideal way to deliver the drug and often lead to patients not adhering to the treatment regimen, since such a regime restricts the patient’s freedom. In addition, many patients are reluctant to accept injections for physiological reasons, and therefore are injected at longer intervals than medically necessary.

Insulin is an example of an important peptide drug when frequent parenteral administration is the most common route of administration. A large percentage, maybe 5%, of the human population suffers from diabetes. The cause of diabetes is impaired production or insufficient production of insulin. Normally, the blood glucose level is constantly monitored by the body's production of natural insulin, but when this does not occur in the case of diabetes, the glucose concentration can rise to high and possibly life-threatening levels. In such cases, insulin must be supplied externally to treat the disease.

Self-administration of insulin is an important reality and part of everyday life for many patients with diabetes. Typically, the patient is required to administer insulin several times a day. Oral insulin is not effective because it is destroyed in the gastrointestinal tract, resulting in systemic concentrations that are too low for a therapeutic effect.

The most common way to administer insulin is by subcutaneous injection, which is done by the patient himself, based on strict monitoring of glucose levels. As mentioned above, frequent injections are not an ideal way to deliver a drug. In addition, there are pharmacokinetic limitations for using the subcutaneous route. The absorption of insulin after subcutaneous injection is rather slow. Sometimes up to one hour passes until the moment when the level of glucose in the blood begins to decrease significantly. This natural problem with subcutaneous insulin delivery cannot be resolved by more frequent administration. To obtain physiologically correct plasma concentrations of insulin, it is necessary to choose a different route of administration.

The delivery of protein and peptide drugs (PPDs) through the nasal passage is usually characterized by a rather low and variable bioavailability. Factors affecting bioavailability from the nasal cavity include limited surface area (approximately 150 cm ² ), large PPDs, mucociliary clearance, and enzymatic destruction. Absorption of PPDs from the nasal cavity can be significantly improved with absorption enhancers. A rather large number of amplifiers has been investigated, and the proposed mechanisms are that they open impenetrable walls, destroy the membrane, or inhibit enzymes. However, permeation enhancers often cause local irritation on the nasal membrane, creating a problem that has been proven to be difficult to solve.

Delivery by inhalation of an aerosol of insulin was documented as early as the 1920s (M. Gänsslen "Uber Inhalation von Insulin"). The natural state for insulin as a drug is, nevertheless, a solution form, so historically, from the 1920s, studies on nasal and pulmonary administration of insulin have been concentrated on various liquid insulin preparations.

Methods for making insulin as a dry powder from a liquid state have been known and have been used for more than 50 years, including methods such as evaporation, spray drying and freeze-drying (lyophilization). However, there were no reliable and economical technologies for producing insulin powders with suitable properties, on the one hand, and suitable apparatus for delivering powder to a user in a way that provides efficient systemic delivery, on the other hand. This interfered with large-scale studies using insulin in dry powder formulations. However, in the early 1990s, Bäckström, Dahlbäck, Edman and Johansson (Therapeutic preparation for inhalation, WO 95/00127) showed that inhalation of a therapeutic drug containing insulin and a absorption enhancer quickly and efficiently leads to insulin absorbed in the lower respiratory tract. Obviously, an amplifier was necessary in all likelihood due to insufficient powder disaggregation and the use of a substandard powder inhaler. Over the past decade, many reports have been published describing the pharmacokinetics and pharmacodynamics of insulin delivered to the human lung. In most known cases, insulin was dispersed from an aqueous preparation. However, in the early 1990s, a study was conducted of the effect of pulmonary administration of insulin in the form of a dry powder. It has been demonstrated that systemic delivery of dry insulin powder can be accomplished by oral inhalation and that the powder can be rapidly absorbed through the alveolar regions of the lungs. For example, in US Pat. No. 5,997,848 it is demonstrated that systemic delivery of dry insulin powder is achieved by oral inhalation and that the powder can be rapidly absorbed through the alveolar regions of the lungs. However, the reverse dissolution of the dose still looks low. According to the description, insulin dosages have a total weight from the lowest value of 0.5 mg up to 10-15 mg of insulin, and insulin is present in individual particles in a concentration of from only 5% to 99% by weight with an average particle size of less than 10 microns.

A number of factors make delivering PPDs to the lungs as dry powders an attractive alternative. PPDs are susceptible to degradation in various ways, including deamination, hydrolysis, and oxidation. Therefore, achieving an acceptable stability of a pharmaceutical product in many cases can be a difficult task. In terms of stability, a solid preparation that is stored under dry conditions is usually the best option. In the solid state, the molecules are usually relatively stable in the absence of moisture or elevated temperature. Proteins and peptides of medium molecular weight are soluble in the liquid layer deep in the lung and, therefore, dissolve, providing rapid absorption from the lung.

As for the presentation of the dose, dry powder systems are available in two main classes: the type of reservoir, where the powder is in the inhaler in the form of a mass of bulk material, and the type of single doses, where the powder is pre-measured in single doses. In the first case, the dose is measured by the patient using the device, and in the second case, the dose is measured and enclosed by the manufacturer in, for example, gelatin capsules or an Al-blister.

A specific case of pre-measured doses are electrostatically or electrodynamically manufactured doses (see US Pat. Nos. 6,089,227, SE 9802648-7, SE 9802649-5 and SE 0003082-5; see also US 6063194, US 5714007, US 6007630 and WO 00/22722 ) The configuration of a dose made by this method may be specialized for a particular application. In addition, there are also great opportunities for the manufacture of powders with a given internal structure, such as porosity, which will affect the adhesion forces between the particles.

A large number of different solutions have been proposed for the disaggregation of drug powder in DPI. One example is the use of a spacer, the principle of which is based on the dispersion of particles evenly distributed in the container, from which inhalation can be made. In principle, the inhaler is connected to a container that has a relatively large volume and into which atomized powder is injected. When inhaled from a spacer, the atomized powder effectively reaches the alveoli. This method, in principle, has two drawbacks: firstly, difficulties in controlling the amount of medicine entering the lung, since an uncontrolled amount of powder sticks to the walls of the spacer, and secondly, difficulties in operating this relatively bulky apparatus.

External sources of energy, in addition to the inspiratory energy that the user makes during inhalation, are common in the art to improve the technical characteristics of the inhaler in terms of disaggregation. Some manufacturers use electric propellers, piezo vibrators, and / or mechanical vibrations to disaggregate agglomerates. The addition of external energy sources complicates and increases the cost of inhalers more than necessary, and also increases the requirements placed on the user for the operation of the inhaler.

Therefore, there is a need for suitable therapeutic drug preparations and a method and system for providing highly effective disaggregation and dispersion of drug powder into the air for administration to a user inhaling it through a new type of inhaler device.

SUMMARY OF THE INVENTION

According to the invention, a dry powder inhaler (8) is provided, comprising:

a nozzle (1) having an inlet and an outlet,

a substrate (140, 141), wherein the nozzle (1) and the substrate (140, 141) are movable relative to each other when air is sucked through the nozzle outlet,

the dose of drug powder (180), deposited on a substrate (140, 141) and having a particle size distribution in aerodynamic sizes, suitable for therapeutic use, and adjustable porosity, characterized in that

the nozzle (1) is configured to create a local high-speed turbulent air stream entering the nozzle inlet outlet, exiting through its outlet when air is sucked in and the relative movement of the nozzle (1) and substrate (140, 141) and crossing the dose at the specified relative movement medicinal powder (180), exposing gradually the indicated dose to shear stresses and inertia forces of the specified air stream and thereby providing for the disaggregation and dispersion of air into the air Gatov particles within said dose (180).

According to one embodiment of the invention, there is provided an inhaler in which said dose of drug powder (180) contains insulin as a pharmacologically active substance.

According to another embodiment of the invention, there is provided an inhaler in which said dose of drug powder (180) contains protein as a pharmacologically active substance.

According to another embodiment of the invention, there is provided an inhaler in which said dose of drug powder (180) contains a peptide as a pharmacologically active substance.

According to another embodiment of the invention, there is provided an inhaler in which said dose of drug powder (180) comprises an alpha-1 proteinase inhibitor, interleukin-1, parathyroid hormone, genotropin, colony-stimulating factors, erythropoietin, interferons, calcitonin, factor VIII, alpha-1- antitrypsin, follicle-stimulating hormones, an LHRH agonist (luteinizing hormone releasing factor) or IGF-1 (insulin-like growth factor I) as a pharmacologically active substance.

According to another embodiment of the invention, there is provided an inhaler in which said dose of drug powder (180) contains a pharmacologically active substance having a systemic effect.

According to another embodiment of the invention, there is provided an inhaler in which said dose of drug powder (180) contains a pharmacologically active substance that has a local effect in the lungs of the user.

Unlike the prior art, the present invention does not require other energy sources than energy from the inspiratory effort exerted by the user in order to achieve a very high degree of disaggregation and efficiently disperse a dose of dry powder into the air.

In order to achieve a very high degree of disaggregation and dispersal of the dose into the air when it is provided and released to a user who is inhaling through a new type of inhaler, the powder in this dose must have an appropriate porosity. The powder preparation used in the process of dose formation should also have a particle size distribution according to their aerodynamic size, suitable for the intended therapeutic use. The powder is preferably dispensed by methods using an electrostatic or electrodynamic field or a combination thereof, but other methods of dose formation are equally possible. Preferably, an elongated dose of a given size and contour is obtained during the dose formation process, as well as with corresponding porosity and interparticle adhesive forces.

The dose is disaggregated and dispersed into the air by a method of cutting the powder with an air flow (a powder Air-razor method), which is implemented in a new type of inhaler device. Under the action of the force with which the user sucks air through the inhaler, air passes through the nozzle, particles in a powder dose become accessible to the nozzle and are gradually disaggregated and scattered into the stream of air entering the nozzle. The gradual disaggregation and dispersion occurs as a result of the relative movement of the nozzle and the elongated dose. In a preferred embodiment, the powder is applied to a substrate, wherein the extended dose accumulated powder typically occupies a portion of a larger area than the nozzle inlet area. Initially, the nozzle is preferably located outside the area occupied by the powder, and the powder does not have access to the nozzle due to relative movement until the air flow into the nozzle created by suction passes the threshold flow rate. Simultaneously with the suction produced by the user, or immediately after it, relative movement begins in such a way that the nozzle gradually passes through a portion of the powder dose. The high rate of air entering the nozzle inlet provides a large shearing force, turbulence and inertia when the flowing air collides with the first prominent point of the contour of the elongated dose section. As a result, particles in aggregates of powder particles adjacent to the inlet of a moving nozzle are released, disaggregated to a very high degree and dispersed, and then carried away by the created air stream passing through the nozzle and further into the airways of the user.

A preferred method for administering a dosage of a therapeutic dry powder containing at least one finely divided pharmacologically active drug substance to a user who is inhaled through a new type of inhaler depends on the choice of a dry powder preparation providing a suitable particle size distribution. In addition, to achieve optimal delivery results to the user, the dose is preferably formed so that it has an elongated contour, suitable porosity and metering qualities for use in an inhaler that implements a device for cutting powder by air flow. Then the result will be the delivery of the dose to the intended site of action in the airways of the user, characterized by the continuous delivery of the dose with a very high degree of disaggregation of particles, whereby the majority of the delivered dose, by weight, will consist of fine particles.

BRIEF DESCRIPTION OF GRAPHIC MATERIALS

The invention, together with additional objects and their advantages, can be better understood by referring to the following detailed description in conjunction with the accompanying graphic materials, in which

Figure 1 illustrates top and side views of a metered dose formed in the form of a strip on the intended area of the non-perforated substrate;

Figure 2 illustrates top and side views of another measured dose formed in the form of a strip on the intended area of the non-perforated substrate;

Figure 3 illustrates top and side views of a metered dose formed in the form of a strip in the intended area of the perforated substrate;

Figure 4 illustrates top and side views of another measured dose, formed in the form of spots on the intended area of the perforated substrate;

Figure 5 illustrates top and side views of another measured dose formed in the form of a strip in the intended area of the perforated substrate;

6 illustrates top and side views of a metered dose, formed in the form of a two-part dose in the intended area, one part on each side of the perforated substrate;

Fig. 7 illustrates a metering element in the form of a cylinder with longitudinal grooves for multiple doses;

Fig. 8 illustrates a cylinder-shaped dosage element with annular grooves for multiple doses;

Fig. 9 illustrates a disc-shaped metering element with radially spaced grooves for multiple doses;

Figure 10 illustrates a dosage element in the form of a sheet with round holes for multiple doses;

11a illustrates a cross-sectional view of a dose sample on the surface of an unperforated substrate and located next to the same side as the dose of the nozzle in the starting position before the dose is released;

11b illustrates a cross-sectional view of a dose sample on the surface of a non-perforated substrate and located adjacent to the same side as the dose of a moving nozzle suctioning powder particles sprayed into the air stream;

12a illustrates a cross-sectional view of a metered dose sample formed as a two-part dose, one part on each side of the perforated substrate, and located adjacent to the first side of the nozzle substrate at the starting position before the dose is released;

12b illustrates a cross-sectional view of a metered dose sample formed in two-part dose, one part on each side of a perforated substrate, and a moving nozzle adjacent to the first side of the substrate, which sucks powder particles on both sides dispersed into the air stream ;

13 illustrates a non-porous non-perforated substrate with a powder dose on it and a nozzle with an elliptical inlet located next to the same side of the substrate as the dose;

Fig. 14 illustrates a side view of a non-porous non-perforated substrate with a powder dose on it and a nozzle sucking powder particles along the line of motion and scattering them into the air stream;

Fig. 15 illustrates an embodiment of a powder shearing method using an air flow, showing a nozzle and a dosage element in relative motion to each other during the release of the powder dose;

Fig. 16 illustrates an embodiment of an inhaler designed for applying a method of cutting powder by a stream of air;

17 illustrates different forces acting on a stationary particle in a stream of air; and

Fig. 18 illustrates in a flow chart the main steps of a dose delivery method.

DETAILED DESCRIPTION

The present invention discloses a dose of a therapeutic dry powder preparation in the form of a pre-prepared medicament powder for inhalation, which is highly disaggregated and entrained in inhaled air by using a powder shearing method to disaggregate and disperse the powder particles into the air.

The drug powder contains one or more pharmacologically active substances, such as proteins or peptides, and possibly one or more excipients. In this document, the terms “powder” or “medicinal powder” are used to refer to a substance in the form of a dry powder, which is the object of disaggregation and dispersion into the air and is intended to precipitate on the selected intended area, site of action, airways of the user. Possible excipients may or may not be disaggregated in the same manner as the active pharmacological substance, depending on the model of powder. For example, an ordered mixture contains an excipient characterized by particles that are significantly larger than particles of a pharmacologically active substance. Additional examples of pharmacologically active substances in dry powder formulations that are of interest for administration by inhalation are the following: ketobemidone, fentanyl, buprenorphine, hydromorphone, ondansetron, granisetron, tropisetron, scopolamine, naratriptan, zolmitriptan, almotriptan, dihydroeroterinerotrin, dihydroeroterinerotrin, dihydroeroterinerotrin, dihydroeroterinerotrin, dihydroerotinerotrinit, calcidineroterinotrinit, calcidineroterinotrinit, calcidineroterinotrinitr, dihydroerotinerotrinit, calcidineroterinotrinitr, calcideroerintrin follicle-stimulating hormone (FSH), insulin, interferons (alpha and beta), parathyroid hormone, alpha-1-antitrypsin, LHRH agonist.

Refer to Fig.1-18 graphic materials, where the same numbers denote the same elements in several types. Six different embodiments of the doses on the substrate are shown in FIGS. 1-6 as examples. Each of FIGS. 1 and 2 illustrates a non-porous non-perforated substrate 141 with a selected marked portion for a dose 160, on which a main elongated dose of the powder 180 is applied in the form of a strip, the dose having a random contour suitable for this application. Figures 3-6 illustrate embodiments similar to the embodiment of Figure 1, but instead of a non-perforated substrate 141, a perforated substrate 140 is shown. A characteristic difference between a perforated or porous substrate 140, on the one hand, and a non-porous or non-perforated substrate 141, on the other hand, is in that the former passes air through the substrate, including the intended dose portion 160, and the latter does not pass air. The choice of substrate type depends on the application and the selected inhaler device. The illustrated doses have elongated contours in the form of a strip with the exception of Figure 4, which illustrates an elongated dose formed as a series of successive spots of the same or different sizes. The substrate (carrier) for doses 140, 141 may be bent if necessary, for example, in order to place a large portion of the dose in the small space of the dosage element reserved for this. Various types of dosage elements 10, each of which is capable of containing a plurality of doses, are shown in FIGS. 7-10. A method for cutting powder by air flow is illustrated in FIGS. 11a, 11b-14, where various embodiments of elongated doses 180 are connected to different substrates 140, 141. These graphic materials illustrate how the relative movement v of the dose and nozzle 1 allows shear forces of the air flow, entering the nozzle inlet, gradually disaggregate and disperse the powder particles 101 into the air 20. FIG. 15 illustrates an embodiment of a method of cutting powder by an air stream implemented in a new type of inhaler, illustrated go also in FIG. 16.

In the preferred embodiment shown by way of example in FIGS. 11a and 11b, the method of cutting off the powder with a powder air stream includes administering a controlled relative movement of an elongated dose of the powder 180, such as insulin, applied to the substrate 141 used as the dose support member, and an appropriately mounted nozzle 1, which collects and directs a local high-speed air stream 20. When the nozzle inlet is directed to a mass of powder on a substrate, the energy of the air flow, which is Xia result of suction force disaggregates and disperses into air the particles 101 available powder, located on the substrate. As the nozzle moves in the direction of the elongated contour of the applied dose powder, primary particles and particle aggregates gradually become available and are exposed to shear and inertia forces of the air flow moving into the nozzle. Thus, as a result of cutting off by a stream of air, individual particles are gradually disaggregated, released, scattered, and entrained in the air entering the nozzle. However, the final therapeutic effect is largely dependent on the powder preparation and the characteristics of the initial particles. To achieve the optimal therapeutic effect, it is necessary that the initial particles be of a certain average size and have a certain size distribution and be completely disaggregated upon delivery. Only then, a large proportion of the delivered dose will settle in the intended area of the user's airways, that is, at the site of the therapeutic action. Delivery may be by nasal or oral administration, depending on what type of inhaler device is used.

The degree of particle aggregation and dose porosity play an important role in obtaining the best fine fraction and achieving the best dispersion of the powder into the air as it is forcibly entrained in the air as a result of the release. Finely divided medicinal powders with an initial particle size below 10 microns are exceptionally fluid, but tend to form aggregates. Therefore, finely divided powders, which are less inclined to form aggregates and / or require less energy for the destruction of the formed aggregates, are preferable when using the method of cutting the powder by air flow. For example, to facilitate the disaggregation and dispersion of active substances into the air, porous particles or ordered mixtures may be used, which may possibly contain pharmacologically acceptable excipients, used, for example, to dilute the active substance or to improve one or more properties of the active substance, such as bioavailability or electrostatic properties.

Unlike the prior art, where the powder in a dose intended for inhalation is usually in the form of a highly aggregated mass of powder, the dose of the present invention has a highly porous structure. Therefore, interactions, such as adhesion, between different particles are much weaker than in the prior art. In addition, in a preferred embodiment, the dose is also characterized by an elongated macroscopic shape, the spatial size of which in at least one dimension is several times larger than in other dimensions. These qualities provide a dose of powder that is much easier to disperse.

In an example of a preferred method for generating a metered dose containing, for example, PPDs, an electrostatic or electrodynamic field application method or a combination thereof is used to apply electrically charged particles of a drug powder to a substrate, such as an electrostatic cartridge or a dosage element. The dose thus formed has suitable properties in terms of the occupied area, powder contour, particle size, mass, porosity, adhesion, etc. for easy disaggregation and dispersion of the powder into the air by cutting the powder with an air stream. However, in the prior art, there are other methods of forming a dose of powder, for example, mechanical, pneumatic or chemical methods that are suitable for forming a dose of a medicinal powder, and such doses are suitable for using the method of cutting the powder by air flow. For example, doses can be obtained by traditional methods of volumetric or weight dosing, possibly followed by treatment of these doses with energy. The purpose of supplying energy, for example by vibration or by applying a pulse, is to give the dose optimal spatial and porous characteristics that are suitable for using the method of cutting powder with an air stream.

An example of a suitable powder for use in an inhaler is electric powder. "Electropowder" is defined as a prepared dry powder medicinal substance with or without one or more excipients that meets the set of requirements of electrical conditions for optimal electrostatic dose-forming characteristics. See SE 0002822-5, which is incorporated herein by reference, for details.

An example of a suitable dose of drug powder formed on a support for use in an inhaler is an electrodose. The term "electrodose" as set forth in SE 0003082-5, which is incorporated herein by reference, refers to a dose of a pre-measured medicinal powder intended for use in a dry powder inhaler. An electric dose is formed from an electric powder containing an active powder substance or a dry powder drug with or without one or more excipients, this electrodose being formed on a substrate that is part of a dosage element.

A preferred embodiment of the dose forming methods comprises transferring charged particles of the drug powder discharged from the particle generator to the intended region of the substrate. The particle transfer electrode is organized in the form of an electric iris diaphragm and a shutter with an associated electric field for transferring electrically charged powder particles from the particle generator to the intended area of the substrate, on which a pre-measured dose of the powder should be applied, and thus controlling the direction and speed of the particles in the process of dose formation. An electric iris / shutter is placed between the particle generator and the substrate, so that all particles must pass through the iris, transferred to the substrate. This iris also acts as a shutter. With the adjusted amplitude and frequency of the applied AC voltage, the charged particles will vibrate in the created alternating electric field, and only small light particles will leave the iris diaphragm / shutter for subsequent transfer during dose formation. Moreover, at the adjusted amplitude and frequency, most of the passing charged particles are accelerated and decelerated synchronously with the alternating electric field and, accordingly, hit the intended target portion of the substrate with a low speed and low momentum, which leads to the desired dose porosity. By moving the substrate perpendicular to the center line of the diaphragm / shutter during the dose formation process, it is possible to form an elongated dose of any geometric contour on the substrate. This makes it possible to vary not only the dose porosity, but also the size of the dose site so that the elongated dose matches the selected inhaler and meets the intended medical requirements.

The accumulated mass of active drug particles in a dose that is dispersed into the inhaled air by cutting the powder with an air stream can be disaggregated to at least 40% of the fine fraction (FPF) by weight based on the available active drug particles in a dose of powder. Preferably, said powder mass can be disaggregated to at least 50% FPF and more preferably at least 60% FPF by air flow shearing. In the context of this document, FPF is defined as the mass fraction of delivered active drug particles with a maximum aerodynamic particle size of 5 μm.

Dosing element 10 can be performed in many different ways (Fig.7-10), which are suitable for various types of inhalers. The dosage element may carry one or more doses on substrates 140, 141, as described in the Swedish patent of the present inventors SE 504458 C2, which is incorporated herein by reference. In all cases, suitable substrates may be selected from electrically conductive, dissipative or insulating materials or combinations of different such materials to obtain optimal inhalation characteristics of a metered dose 180 of a particular drug.

Particle adhesion

Particles adjacent to other particles or to the substrate can adhere to each other. The total adhesive force between a particle and its environment, whether it is another particle, an aggregate of particles, a substrate or a combination thereof, will include adhesive forces of many different types. The types of adhesive forces acting on a particle can be Van der Waals forces, capillary forces, electric forces, electrostatic forces, etc. The relative magnitudes and ranges of these forces vary depending, for example, on the material, environment, size and shape of the particle. Here, the term “adhesive force” refers to the sum of all these forces acting on a particle,

Particle disaggregation and entrainment

The main goal of the method of cutting powder by air flow is to disaggregate and entrain the applied particles into the air stream. Particles can be deposited on a substrate in layers, so that some particles will be in contact with the substrate, while others will only be in contact with other particles. Complete disaggregation is the separation of all particles from each other. The separation of particles from their environment includes overcoming the adhesive force, as well as the friction forces acting on the particle.

17 illustrates forces acting on a particle. The force of the air flow 303, acting on the particle 101, is divided into two parts: the attracting force 305, acting parallel to the air flow, and the lifting force 304, acting perpendicular to the air flow. The condition for the release of particles in a static state is that the lifting and attracting forces prevail over the adhesion forces 301 and friction 302.

To completely or almost completely disaggregate particles, it is not enough to apply enough force to the particles to release and entrain. If a significant force acts on the particle aggregate in such a way that more or less the same force acts on all particles, then the aggregate will be entrained in the air flow without being disaggregated. Therefore, the disaggregation condition can be formulated as follows: the difference in external forces acting on two particles must exceed the adhesion and friction forces that hold the particles together. Differences in the strength of the air flow can be effectively achieved by applying shearing forces, and the method of shearing with air flow creates shear forces in the area of the powder deposited, for example, on the substrate.

The following basic principles are used to create a high shear stress and, accordingly, the impact of significant shear forces on particles in the method of shearing by air flow:

- high speed air flow;

- flow lines close to the wall;

- turbulent flow (side effect of high speed).

Increase inertia

The low pressure created by suction through the nozzle causes air to flow in the direction of the low pressure region. The increase in inertia means the acceleration of the mass in the system, that is, the mass of the air itself, with the development of the required high speed air flow after a period of acceleration. The flow rate increases to the point at which the hydraulic resistance makes a further increase impossible if the low pressure level does not decrease, i.e. the pressure drop does not increase or the hydraulic resistance does not decrease.

Shear force propagation

The zone of disaggregation under the action of significant shear forces is concentrated near the nozzle wall. This concentrated area is small compared to the dose area on the substrate, especially if the dose contains a fine powder of high porosity. Inducing the relative movement of the nozzle and dose allows a small and concentrated area of high shear stress to pass through the area occupied by the dose. Depending on the actual spatial distribution of the powder in an extended dose and the distance perpendicular to the direction of movement between the powder and the nozzle inlet, it may turn out that the nozzle is in contact with part of the powder. This does not affect the effectiveness of the method of cutting the powder by air flow. In addition, the movement of the nozzle relative to the powder dose will not affect the speed of the air flow, since the relative speed of movement is much lower than the speed of the air flow entering the nozzle inlet. The movement of the nozzle forces the position of the moving low-pressure region relative to the contour of the elongated dose in the direction of movement. Thus, the zone of high shear forces moves along a path controlled by the relative movement of the nozzle, resulting in high shear forces that gradually disperse the powder particles into the air. Even if there is some contact between the nozzle and the powder, the powder quickly dissipates into the air without affecting the speed of relative motion (see Fig. 14, illustrating the case where the line of movement 2 of the inlet of the nozzle 3 partially contacts the powder 180). Preferably, this path starts from the outside immediately after the contact point between the zone of high shear forces of the air flow and the boundary of the powder dose loop and follows the outline of the loop from start to finish. The relative motion induced between the nozzle and the dose of the powder helps to achieve and maintain the necessary conditions established for the disaggregation of the entire dose of the powder, and not just its part. The main advantages that relative movement provides are the following:

- during the initial phase of acceleration, inertia occurs, ensuring a high air flow rate;

- shear forces near the wall extend over a large area over time;

- efficient use of energy.

Thus, the gradual disaggregation and dispersal of the medicinal powder is an essential essential sign of dose delivery using the air flow shearing technique.

Energy efficiency

The dosage time interval for disaggregating and dispersing the powder by cutting with an air stream, depending on the application, can be selected within the time interval of inhalation. Most prior art inhalers use a user's inspiratory force for only a short period. This means that the total energy used for disaggregation is accordingly low in these inhalers if external energy is not supplied for disaggregation. The time interval for delivery by cutting with an air stream can be set, for example, up to 1 second, which means that the inspiratory force during this full second is used to disaggregate the particle aggregates.

The first task of the air-shearing method is the release of individual fine particles into the air, that is, overcoming adhesive forces, such as Van der Waals forces, electrostatic, gravitational forces, friction forces, etc., connecting the particle with other particles in powder aggregates and / or with the surface of the substrate. The second task of the air flow shear method is to direct all particles in the air into the nozzle with the loss of as few particles as possible. Particles entering the nozzle must then be transported with air into the airways of the user using an appropriately organized flow channel. To solve these problems, an energy source is required. It has been unexpectedly discovered that the available driving force as a result of the suction force by inhalation, which the user makes, provides sufficient energy to cut the powder with an air stream. It is shown that the normal inspiratory force produced by an adult user can create a low pressure region approximately in the range of 1-8 kPa. Although pressure within such ranges is acceptable, in a preferred embodiment, the range is 1-4 kPa to facilitate use by most people. The experiments showed that the limited reduced pressure or the motive pressure produced in this way can be used with high efficiency without using external energy sources during the inhalation process. Despite the fact that the method of cutting the powder by air flow works equally well using an external energy source, which partially or completely replenishes the absorption energy, an external energy source does not give any advantages and therefore is superfluous. However, the relative motion of the powder and the nozzle necessary to use the method of cutting the powder with an air stream is preferably not due to the energy from the inhalation force, although this is entirely possible. Instead, the relative movement can be organized in many different ways, including, for example, the use of mechanisms containing spring elements capable of retaining the potential energy supplied by the user during operation of the inhaler device.

In general, in a preferred embodiment, the nozzle moves from its initial position to its final position, passing through the entire dose-occupied area in one turn. Preferably, the nozzle's initial position is outside the occupied area at a distance “s” (s≥0 + nozzle orifice size) to allow suction-initiated airflow to form through the nozzle before the relative movement brings the nozzle to an adjacent powder position. In such a preferred embodiment, the energy and shear force generated by cutting the powder by the air flow are set before they reach the boundary of the elongated dose circuit and begin to attack the aggregates of the powder particles. A further improvement in the method of cutting off the powder by air flow is to introduce a suction-related start of the flow into the nozzle so that the resulting air velocity is high enough to achieve the desired effect of cutting the powder by air flow.

In comparison, in many prior art inhaler devices, the powder release cycle begins with the introduction of the powder into the channel connecting the air inlet and the mouthpiece outlet at the end. The powder is thus surrounded by a volume of still air. This significant amount of air is then accelerated by the suction force, usually produced by the user, sometimes additionally amplified by energy from an external source, for example by vibrating the medicinal powder or by applying an additional stream of air under pressure. All powder is subjected to this treatment at the same time, which leads to unsatisfactory disaggregation of the entire mass of powder entrained in air. Briefly, this means poor performance, since not all powder is subjected to shearing forces at the level necessary for disaggregation to actually occur. Further, since the speed of the air surrounding the powder is zero at the initial moment of the release process, some aggregates of particles in the powder will collapse randomly during the acceleration phase if the shear force of the air flow is not strong enough to disaggregate the aggregates, and, accordingly, they are delivered in the form of whole aggregates . Within the published specifications, according to the present invention, in which the method of cutting the powder by air flow from a pre-prepared dose of therapeutic dry powder is used, all powder available to the moving nozzle is actually exposed to the shearing force necessary to disaggregate.

EXAMPLES OF TESTS

A. Test result for insulin, from the group of polypeptides

The following in vitro experiment was conducted using a micronized, finely divided human insulin powder containing 50 wt.% Particles with an initial particle size of less than 2.16 microns and 90 wt.% Less than 3.81 microns to study the method of cutting the powder by air flow as applied to insulin. .

Table 1 Impactor Anderson Flow-adjusted cutoff particle size, microns Measured mass by HPLC, mcg The cumulative distribution in the impactor,% Inlet + Pre-Impact 22,20 100.0 Stage 0 7.66 0.00 97.5 Stage 1 6.90 0.00 97.5 Stage 2 4.44 93.50 97.5 Stage 3 3.60 390.20 87.0 Stage 4 2,53 311.20 43.1 Stage 5 1,61 63.10 8.1 Stage 6 0.84 8.70 1,0 Stage 7 0.54 0.00 0,0 Filter <0.31 0.00 0,0

A strip-shaped insulin dose of approximately 3 mm wide and 15 mm long and weighing approximately 1034 μg was formed on a substrate using an electrodynamic field-forming method. Then this substrate was placed in a new type of inhaler containing an air-cutting device for disaggregating and dispersing a powder dose. The mouthpiece of the inhaler was connected to the Anderson impactor. Then, absorption was carried out through the mouthpiece, providing an air speed of 48.2 liters per minute through the inhaler and into the impactor. The dose was dispersed in the air flow going to the impactor, and delivered in about one second. The powder of this dose settled on the steps of the impactor. The distribution of fine particles of the delivered mass at different stages of the impactor is shown in Table 1. Accumulation on the substrate and in the relevant parts of the inhaler connected to the impactor was determined to be 145.4 μg.

It was determined that the delivered dose was 888.9 mcg. All masses were determined by HPLC. It was determined that the fine fraction, less than 5 microns, amounted to 97.5% of the delivered mass and 83.8% of the total determined mass.

B. Test result for insulin, from the group of polypeptides

For an additional study of the method of cutting off the air flow in relation to the dose of insulin, the following in vitro experiment was carried out using a powder from the same batch of micronized, finely ground human insulin powder, as in experiment A. Insulin contained 50 wt.% Particles with an initial particle size of less than 2 , 16 microns and 90 wt.% Less than 3.81 microns.

This time, a dose of insulin in the form of a strip of approximately 3 mm wide and 15 mm long and weighing approximately 1220 μg was formed on a substrate using a mechanical formation method. The dose was weighed and then applied to a substrate that vibrated to evenly distribute the dose on the substrate and to create porosity. Then, the substrate was inserted into a new type of inhaler containing an air-cutting device for disaggregating and dispersing a powder dose. The mouthpiece of the inhaler was connected to the Anderson impactor. Then, suction was made through the mouthpiece, providing an air speed of 45.4 liters per minute through the inhaler and into the impactor. The dose was dispersed in the air flow going to the impactor, and delivered in about one second. The powder of this dose settled on the steps of the impactor. The distribution of fine particles of the delivered mass at different stages of the impactor is shown in Table 2. Accumulation on the substrate and in the relevant parts of the inhaler connected to the impactor was defined as 195.1 μg. It was determined that the delivered dose was 676.5 μg. All masses were determined by HPLC.

table 2 Impactor Anderson Flow-adjusted cutoff particle size, microns Measured mass by HPLC, mcg The cumulative distribution in the impactor,% Inlet + Pre-Separator 102.7 100.0 Stage 0 7.90 2.6 84.8 Stage 1 7.11 25.0 84,4 Stage 2 4,58 108.9 80.7 Stage 3 3.71 237.0 64.6 Stage 4 2.61 146.2 29.6 Stage 5 1,66 37.3 8.0 Stage 6 0.87 9.5 2,5 Stage 7 0.55 7.3 1,1 Filter <0.32 0,0 0,0

It was determined that a finely divided fraction, less than 5 microns, amounted to 81.5% of the delivered mass and 63.2% of the total defined mass.

C. Test result for terbutaline, an example of an organic molecule

Terbutaline sulfate was chosen to study the air-flow shearing method for a well-known therapeutic substance because it is a topically active drug and is sold in powder form for use in inhalers. Turbohaler® was purchased containing 50 mg of Bricanyl® (terbutaline sulfate), which is used against asthma as a bronchodilator that stimulates β ₂ receptors.

The following in vitro experiment was conducted at a different point in time after A and B using Turbohaler® terbutaline micronized drug powder. Doses of the powder were formed on substrates using the method of formation in an electrodynamic field. Doses were formed in the form of strips of approximately 3 mm wide and 15 mm long. A dose of approximately 2239 μg was used in the present experiment. The substrate was placed close to the nozzle, and its inlet was on the same side of the substrate as the dose. The diameter of the nozzle opening was slightly larger than the dose width. The area of the nozzle inlet was significantly smaller than the area occupied by the elongated dose. The nozzle outlet was connected to the Anderson impactor. Then, suction was made through the nozzle outlet and the air flow was allowed to stabilize at an air speed of 45.2 liters per minute, after which the substrate was moved in the direction of the nozzle parallel to the dose band so that the dose was sequentially sucked by the air flow going into the nozzle and delivered to the impactor . The dose was delivered in about one second. Dose powder settled on the steps of the impactor. The distribution of particles of the delivered mass at different stages of the impactor is shown in Table 3. Accumulation on the substrate and in the relevant parts of the inhaler connected to the impactor was determined to be 151.2 μg. It was determined that the delivered dose was 2088 mcg. All masses were determined by HPLC.

Table 3 Impactor Anderson Flow-adjusted cutoff particle size, microns Measured mass by HPLC, mcg The cumulative distribution in the impactor,% Inlet + Pre-Separator > 8 516.2 100.0 Stage 0 7.12 55.6 75.3 Stage 1 4,59 121.3 72.6 Stage 2 3.72 182.1 66.8 Stage 3 2.61 483.1 58.1 Stage 4 1,66 366.6 35.0 Stage 5 0.87 277.6 17.4 Stage 6 0.51 49.4 4.1 Stage 7 0.34 9.1 1.7 Filter <0.3 27,2 1.3

By interpolation between steps 0 and 1, it was determined that the finely dispersed fraction, less than 5 μm, amounted to 73% of the delivered mass and 68% of the total determined mass.

These experiments show that the air-flow shearing method for a suitably adapted and prepared dose of drug powder formed on a substrate can give very good efficiency in delivering a dose with a very high yield of the finely divided fraction to the user. As shown in experiment B, very good results can be achieved from a simply adapted dose (in this case, insulin) by using the method of cutting the powder by air flow to disaggregate and disperse it, even if the preferred method of dose formation in an electrostatic or electrodynamic field gives better results from the point of view of disaggregation and dose dispersion by air flow shearing.

As a result of optimization of the adhesive force in the deposited powder between particles and between particles and the substrate, as a result of optimization of the powder zone, as a result of optimization of the nozzle geometry and as a result of optimization of the relative velocity of the nozzle and powder, the disaggregation and, consequently, the mass of the finely dispersed fraction with particles smaller than or equal to 5 microns, approach very close to 100% of the mass of available medicinal powder.

By regulation "v" it is meant that the most suitable dosing time interval can be defined as the interval during which delivery of a spatially extended dose should occur. The time interval for dosing depends on several factors, for example, the intended area of the respiratory tract, the nominal mass of powder loading and the type of user for treatment. From the start point to the end point, the relative movement of the dose / nozzle should take place over a specific time interval, which usually ranges from 0.01 to 5 seconds. The time distribution should be selected in accordance with the application, that is, the points in time should be selected when the movement begins and ends within the interval of time for air intake that takes place.

Therefore, it is important to optimize the delivery of the dose of the prepared medicinal powder using a new type of inhaler device that takes full advantage of the method of cutting the powder with air flow. An embodiment of such a new inhalation device is disclosed in FIG. This method optimizes dose delivery, taking full advantage of the described new method of cutting powder with an air stream as applied to the dose of a suitably prepared medicinal powder.

Specialists in the art should understand that in the present invention can be made various modifications and changes within its scope, which is defined by the attached claims.

Claims (7)

1. An inhaler (8) of a dry powder containing a nozzle (1) having an inlet and an outlet, a substrate (140, 141), wherein the nozzle (1) and the substrate (140, 141) are movable relative to each other when air is sucked through the nozzle outlet, the dose of drug powder (180), deposited on a substrate (140, 141) and having a particle size distribution in aerodynamic sizes, suitable for therapeutic use, and adjustable porosity, characterized in that the nozzle (1) is configured to create a local high-speed turbulent air stream entering the nozzle inlet outlet, exiting through its outlet when air is sucked in and the relative movement of the nozzle (1) and substrate (140, 141) and crossing the dose at the specified relative movement medicinal powder (180), exposing gradually the indicated dose to shear stresses and inertia forces of the specified air stream and thereby providing for the disaggregation and dispersion of air into the air Gatov particles within said dose (180). 2. The inhaler according to claim 1, characterized in that said dose of the medicinal powder (180) contains insulin as a pharmacologically active substance. 3. The inhaler according to claim 1, characterized in that said dose of the medicinal powder (180) contains protein as a pharmacologically active substance. 4. The inhaler according to claim 1, characterized in that the specified dose of the medicinal powder (180) contains the peptide as a pharmacologically active substance. 5. The inhaler according to claim 1, characterized in that the specified dose of the medicinal powder (180) contains an alpha-1 proteinase inhibitor, interleukin-1, parathyroid hormone, genotropin, colony-stimulating factors, erythropoietin, interferons, calcitonin, factor VIII, alpha 1-antitrypsin, follicle-stimulating hormones, LHRH agonist (luteinizing hormone releasing factor) or IGF-I (insulin-like growth factor I) as a pharmacologically active substance. 6. The inhaler according to claim 1, characterized in that the specified dose of the medicinal powder (180) contains a pharmacologically active substance that has a systemic effect. 7. Inhaler according to claim 1, characterized in that the specified dose of the medicinal powder (180) contains a pharmacologically active substance that has a local effect in the lungs of the user.

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